Cancer is a broad group of various diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream. According to the National Cancer Institute (NCl), which tracks such statistics, the number of estimated new cases of cancer in the United States in 2012 is 1,638,910 (not including non-melanoma skin cancers), and the number of deaths per year from cancer in the United States is estimated to be 577,190(http://cancer.gov/cancertopics/cancerlibrary/what-is-cancer). Management and treatment options for cancer exist. The primary ones include surgery (e.g., surgical resection of a tumor), chemotherapy, radiation therapy, targeted cancer therapies (e.g., small molecule drugs or monoclonal antibody therapies that specifically target molecules involved in tumor growth and progression), and palliative care, or some combination thereof (collectively referred to herein as “anti-cancer therapies”).
Additional therapies for cancer include therapeutic strategies for inducing, enhancing or suppressing an immune response, collectively called “immune therapies” or “immunotherapies” (which may also be generally referred to herein as “immune response generating therapies”). Recently, immune therapies have become more relevant in the treatment of advanced or metastatic solid tumors. Immunotherapy for use in cancer is generally designed to augment or stimulate the patient's own immune response to better control or eliminate cancerous cells, and may additionally support other treatments such as chemotherapy, surgery, radiation therapy and the use of targeted cancer therapies. Some examples of such immunotherapies for use in oncology include: (1) PROVENGE® (Dendreon), in which dendritic cells are stimulated to activate a cytotoxic response towards an antigen for use in advanced castrate resistant prostate cancer; (2) adoptive transfer of T cells to activate cytotoxic response to cancer; (3) genetically engineering T cells by introducing a virus that introduces a T cell receptor that is designed to recognize tumor antigens; (4) Algenpantucel-L, a cancer vaccine comprised of irradiated allogeneic pancreatic cancer cells transfected to express murine alpha-1,3-galactosyltransferase with potential antitumor activity; (5) viral vector-based immunotherapy; and (6) yeast-based immunotherapy.
Yeast-based immunotherapy is also referred to as TARMOGEN® (GlobeImmune, Inc., Louisville, Colo.) technology, and generally refers to a yeast vehicle expressing one or more heterologous target antigens extracellularly (on its surface), intracellularly (internally or cytosolically) or both extracellularly and intracellularly. Yeast-based immunotherapy technology has been generally described (see, e.g., U.S. Pat. No. 5,830,463). Certain yeast-based immunotherapy compositions, and methods of making and generally using the same, are also described in detail, for example, in U.S. Pat. Nos. 5,830,463, 7,083,787, 7,736,642, Stubbs et al., Nat. Med. 7:625-629 (2001), Lu et al., Cancer Research 64:5084-5088 (2004), and in Bernstein et al., Vaccine 2008 Jan. 24; 26(4):509-21, each of which is incorporated herein by reference in its entirety. Yeast-based immunotherapy for cancer is described, for example, in U.S. Pat. Nos. 7,465,454, 7,563,447, 8,067,559, 8,153,136, U.S. Patent Publication No. 2009-0098154, and PCT Publication No. WO 07/133,835, each of which is incorporated herein by reference in its entirety.
Yeast-based immunotherapy has a unique ability, as compared to other immunotherapies, to induce innate immune responses as well as a wide range of adaptive immune responses against the target antigen, including CD4-dependent TH17 and TH1 T cell responses and antigen-specific CD8+ T cell responses, which include cytotoxic T lymphocyte (CTL) responses, all without the use of exogenous adjuvants, cytokines, or other immunostimulatory molecules, many of which have toxicity issues. In addition, yeast-based immunotherapy compositions inhibit regulatory T cell (Treg) numbers and/or functionality, thereby enhancing effector T cell responses that might normally be suppressed by the presence of the tumor, for example. Moreover, as compared to immunotherapeutic compositions that immunize by generating antibody responses, the antigen-specific, broad-based, and potent cellular immune responses elicited by yeast-based immunotherapy are believed to be particularly effective in targeting tumor cells, even in the face of what may otherwise be a suppressive environment. Since this type of immunotherapy utilizes the natural ability of the antigen presenting cell to present relevant immunogens, it is not necessary to know the precise identity of CTL epitopes or Class II MHC epitopes of a target antigen to produce an effective yeast-based immunotherapeutic, nor is it necessary to isolate any immune cells from the patient to produce the immunotherapeutic. In fact, multiple CD4+ and CD8+ T cell epitopes can be targeted in a single yeast-based immunotherapeutic composition, and so the use of algorithms and complex formulas to identify putative T cell epitopes or T cell receptors is eliminated.
One series of yeast-based immunotherapy products, including the TARMOGEN® product candidates known as “GI-4000” currently in clinical development by GlobeImmune, Inc., has been developed to stimulate immune responses against a mutated Ras protein expressed by a patient's tumor. “Ras” is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction). Ras mutations are found in approximately 180,000 new cancer cases each year in the United States across a spectrum of tumor types, including pancreas, non-small cell lung cancer (NSCLC), colorectal, endometrial and ovarian cancers, as well as melanoma and multiple myeloma. Studies have shown that tumors with Ras mutations are generally less responsive than tumors with normal Ras to conventional chemotherapy as well as targeted agents. For some cancers, such as NSCLC or colorectal cancer, therapies that target epidermal growth factor receptor, or EGFR, have improved clinical outcomes. However, the presence of a Ras mutation in the tumor has been associated with poor prognosis despite use of EGFR targeted therapies in colorectal cancer. Similarly, other studies have shown that patients with Ras-mutated colorectal tumors do not benefit from cetuximab therapy, another EGFR targeted agent, compared to patients with normal Ras, who have improved survival rates when treated with the same therapy. As a result, patients with Ras mutations have fewer available effective treatment options. The targeted reduction of cells containing Ras mutations could result in improved clinical outcomes for patients with a number of human cancers due to the role mutated Ras plays in tumor growth. However, there are presently no available therapies targeting mutated Ras in late-stage clinical trials.
Progress in the field of immunotherapy has been slow, but recent clinical successes have given strong support to the potential of this approach as a treatment modality in cancer. However, there is a need in the art to define biomarkers which identify patients who will obtain clinical benefit from immune-based treatment in cancer and identify clinical responders and non-responders, in advance of treatment. Examples of immunotherapy markers include CD54 expression and interleukin 12p70 production, but they have not been fully validated. Also used are several cellular immune marker assays (cytokine flow cytometry, MHC tetramers, and enzyme-linked immunosorbent spot (ELISPOT)). It is important to note that assays predicting benefit from immunotherapies need to be standardized to produce reproducible and comparable results. This has not been done in this area.
There is a need in the art for practical, useful tests for determining, in advance of treatment, whether a given cancer patient is likely to benefit from administration of immune response generating therapies, either alone or in combination with other anti-cancer drug therapies, or, conversely whether such treatment is not likely to benefit a given cancer patient. This invention meets this need.
Further prior art of interest relating to ability to predict cancer patient benefit from certain types of drugs includes U.S. Pat. Nos. 7,736,905, 7,858,390; 7,858,389, 7,867,775, 8,024,282; 7,906,342 and 7,879,620, and pending U.S. patent application Ser. No. 13/356,730 filed Jan. 24, 2012, and U.S. patent application Ser. No. 12/932,295 filed Feb. 22, 2011, published as US 2011/0208433, all of which are assigned to Biodesix, Inc. The '905 patent and U.S. patent application Ser. No. 12/932,295 filed Feb. 22, 2011 are incorporated by reference herein. The '905 patent describes, among other things, a mass spectrometry based test for determining whether NSCLC cancer patients are likely to benefit from epidermal growth factor receptor (EGFR) targeting drugs. This test is known in its commercial version as “VeriStrat”; references to “VeriStrat” in the following discussion will be understood to be in reference to the test described in the '905 patent.